Fibroblast growth factors (FGFs) are involved in the regulation of various physiological processes, such as cell proliferation, chemotaxis, and differentiation. The physiological activity of the FGFs is mediated by fibroblast growth factor receptors (FGFRs), which are specific cell surface receptors. FGFRs belong to a receptor protein tyrosine kinase family, and comprise an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. Four types of FGFRs (FGFR1, FGFR2, FGFR3, and FGFR4) have been heretofore identified. FGFRs bind to FGFs to form dimers, and are activated by phosphorylation. Activation of the receptors induces mobilization and activation of specific downstream signal transduction molecules, thereby developing physiological functions.
Many reports have been made about the relationship between aberrant FGF/FGFR signaling and various human cancers (e.g., NPL 1, NPL 2, and NPL 3). Aberrant activation of FGF/FGFR signaling in human cancer is considered to be attributable to an autocrine or paracrine mechanism by overexpression of FGFRs and/or gene amplification, gene mutation, chromosomal translocation, or overproduction of FGFs (ligands). Moreover, such aberrant signaling is considered to be partly responsible for therapeutic resistance to existing chemotherapeutic anticancer drugs or other receptor tyrosine kinase inhibitors in human cancer (NPL 4). Furthermore, the aberrant signaling is known to be associated with various diseases caused by abnormal angiogenic processes, such as solid tumor, rheumatoid arthritis, psoriasis, retinopathy, and age-related macular degeneration (NPL 5).
Accordingly, therapies targeted for FGF/FGFR signaling not only have a direct antitumor effect on tumor cells that are highly dependent on FGF/FGFR signaling, but also exhibit an inhibitory effect on tumor angiogenesis induced by FGF/FGFR signaling; thus, such therapies are expected to be promising targeted therapies having sufficient antitumor effects. In addition, such therapies are expected to provide drug effect enhancers for existing chemotherapeutic anticancer drugs or other receptor tyrosine kinase inhibitors, or effective therapeutic remedies for cancer types that are resistant or unresponsive to these drugs.
PTL 1 discloses a wide range of fused bicyclic compounds having mTOR inhibitory activity; however, the specifically disclosed compounds are all imidazopyrazine compounds, and FGFR inhibitory activity is nowhere mentioned in PTL 1. PTL 2 discloses BTK inhibitor compounds having a characteristic substituent at the 3-position of the pyrazolopyrimidine ring, but is silent about FGFR inhibitory activity. PTL 3 discloses HSP90 inhibitor compounds having a characteristic substituent at the 5-position of the pyrrolopyrimidine ring, but is silent about FGFR inhibitory activity.